Pub Date : 2025-12-04DOI: 10.1038/s41431-025-01981-z
Smadar Horowitz-Cederboim, Ronit Hoffman-Lipschuetz, Ronen Durst, Shoshi Shpitzen, Ayelet Shauer, Donna R Zwas, Chaggai Rosenbluh, Israel Antman, Avital Eilat, Tamar Harel, Orr Tomer, Vardiella Meiner
Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.
{"title":"Reconsidering a silent variant: SGCA's role in atypical cardiomyopathy.","authors":"Smadar Horowitz-Cederboim, Ronit Hoffman-Lipschuetz, Ronen Durst, Shoshi Shpitzen, Ayelet Shauer, Donna R Zwas, Chaggai Rosenbluh, Israel Antman, Avital Eilat, Tamar Harel, Orr Tomer, Vardiella Meiner","doi":"10.1038/s41431-025-01981-z","DOIUrl":"https://doi.org/10.1038/s41431-025-01981-z","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1038/s41431-025-01987-7
Helen Dolling, Sophie Rowitch, Malachy Bromham, Stephanie Archer, Sara O’Curry, David H. Rowitch, F. Lucy Raymond, Claire Hughes, Kate Baker
As early rapid genomic sequencing (rGS) is adopted in paediatric medicine, there is an urgency to understand and address family support needs. This mixed methods study (Peregrin*) examined the experiences of 96 parents, 1–5 years after receiving trio rGS results for their child with a severe early-onset condition. Quantitative outcome measures assessed parental well-being, life satisfaction, and family impact, comparing results to non-clinical population data, between mothers and fathers, and according to child’s diagnostic outcome. Qualitative semi-structured interviews explored parents’ satisfaction with support, engagement with support networks, and unmet needs. Quantitatively, mothers exhibited elevated anxiety and depression relative to population norms, and there was a lack of strong correlation in well-being metrics within couples. Parents of children with a genomic diagnosis reported poorer well-being, explained by greater medical complexity. Qualitatively, insufficient support was more frequently reported by those whose child had received a genomic diagnosis (36%) compared to those without (6%). Families drew on a range of formal and informal support sources, including condition-specific groups, though these were accessed by a minority of fathers. These findings highlight persistent and evolving support needs in families affected by complex childhood health conditions, which persist after rGS. Parents’ support needs are highly individual, vary over time and across children’s illness trajectory. There remain important gaps between parental needs and support, impacting on family well-being.
{"title":"Fathers’ and Mothers’ support needs and support experiences after rapid genome sequencing","authors":"Helen Dolling, Sophie Rowitch, Malachy Bromham, Stephanie Archer, Sara O’Curry, David H. Rowitch, F. Lucy Raymond, Claire Hughes, Kate Baker","doi":"10.1038/s41431-025-01987-7","DOIUrl":"10.1038/s41431-025-01987-7","url":null,"abstract":"As early rapid genomic sequencing (rGS) is adopted in paediatric medicine, there is an urgency to understand and address family support needs. This mixed methods study (Peregrin*) examined the experiences of 96 parents, 1–5 years after receiving trio rGS results for their child with a severe early-onset condition. Quantitative outcome measures assessed parental well-being, life satisfaction, and family impact, comparing results to non-clinical population data, between mothers and fathers, and according to child’s diagnostic outcome. Qualitative semi-structured interviews explored parents’ satisfaction with support, engagement with support networks, and unmet needs. Quantitatively, mothers exhibited elevated anxiety and depression relative to population norms, and there was a lack of strong correlation in well-being metrics within couples. Parents of children with a genomic diagnosis reported poorer well-being, explained by greater medical complexity. Qualitatively, insufficient support was more frequently reported by those whose child had received a genomic diagnosis (36%) compared to those without (6%). Families drew on a range of formal and informal support sources, including condition-specific groups, though these were accessed by a minority of fathers. These findings highlight persistent and evolving support needs in families affected by complex childhood health conditions, which persist after rGS. Parents’ support needs are highly individual, vary over time and across children’s illness trajectory. There remain important gaps between parental needs and support, impacting on family well-being.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"260-269"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01987-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1038/s41431-025-01985-9
Michaela Cormack
{"title":"When clinical genetics turns the risk lens on itself.","authors":"Michaela Cormack","doi":"10.1038/s41431-025-01985-9","DOIUrl":"10.1038/s41431-025-01985-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1038/s41431-025-01986-8
Marieke J. H. Coenen, Marga Nijenhuis, Bianca Soree, Nienke J. de Boer-Veger, Anne Marie Buunk, Henk-Jan Guchelaar, Elisa J. F. Houwink, Arne Risselada, Gerard A. P. J. M. Rongen, Jesse J. Swen, Daan J. Touw, Roos van Westrhenen, Vera H. M. Deneer, Ron H. N. van Schaik
The Dutch Pharmacogenetics Working Group (DPWG) describes gene-drug interactions to facilitate pharmacogenetic implementation in clinical practice. The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). Evidence based recommendations were obtained via a literature review of published studies. This literature review showed that gene variants leading to a decreased activity of TPMT and/or NUDT15 result in higher risk of toxicities, especially bone-marrow depression. For intermediate metabolisers (IM) of TPMT or NUDT15, it is advised to start with 50% of the normal dose when treated with azathioprine or 6-mercaptopurine. For poor metabolisers (PM), it is advised to start with an alternative treatment or to reduce the dose to 10% of the normal dose. For thioguanine, a dose of 75% of the normal dose is advised for TPMT IM and 50% of the normal dose for NUDT15 IM. Alternative treatment or a start dose reduction is advised for PM. A start dose of 6-7% can be used for TPMT PM and of 10% for NUDT15 PM. For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM. DPWG classifies genotyping for TPMT and NUDT15 “essential” before thiopurine initiation.
{"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between TPMT/NUDT15 and thiopurines","authors":"Marieke J. H. Coenen, Marga Nijenhuis, Bianca Soree, Nienke J. de Boer-Veger, Anne Marie Buunk, Henk-Jan Guchelaar, Elisa J. F. Houwink, Arne Risselada, Gerard A. P. J. M. Rongen, Jesse J. Swen, Daan J. Touw, Roos van Westrhenen, Vera H. M. Deneer, Ron H. N. van Schaik","doi":"10.1038/s41431-025-01986-8","DOIUrl":"10.1038/s41431-025-01986-8","url":null,"abstract":"The Dutch Pharmacogenetics Working Group (DPWG) describes gene-drug interactions to facilitate pharmacogenetic implementation in clinical practice. The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). Evidence based recommendations were obtained via a literature review of published studies. This literature review showed that gene variants leading to a decreased activity of TPMT and/or NUDT15 result in higher risk of toxicities, especially bone-marrow depression. For intermediate metabolisers (IM) of TPMT or NUDT15, it is advised to start with 50% of the normal dose when treated with azathioprine or 6-mercaptopurine. For poor metabolisers (PM), it is advised to start with an alternative treatment or to reduce the dose to 10% of the normal dose. For thioguanine, a dose of 75% of the normal dose is advised for TPMT IM and 50% of the normal dose for NUDT15 IM. Alternative treatment or a start dose reduction is advised for PM. A start dose of 6-7% can be used for TPMT PM and of 10% for NUDT15 PM. For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM. DPWG classifies genotyping for TPMT and NUDT15 “essential” before thiopurine initiation.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"152-160"},"PeriodicalIF":4.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41431-025-01978-8
Qing Lin, Dylan Verden, John Christodoulou, Wendy A Gold, Simranpreet Kaur
KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.
{"title":"KIF1A-associated neurological disorders: therapeutic opportunities and challenges.","authors":"Qing Lin, Dylan Verden, John Christodoulou, Wendy A Gold, Simranpreet Kaur","doi":"10.1038/s41431-025-01978-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01978-8","url":null,"abstract":"<p><p>KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1038/s41431-025-01983-x
Ananília Silva, Sadegheh Haghshenas, Liselot van der Laan, Michael A. Levy, Raissa Relator, Haley McConkey, Jennifer Kerkhof, Steve A. Skinner, Laurence Faivre, James Lespinasse, Antonio Vitobello, Irene Valenzuela, Ingrid E. Scheffer, Sophie J. Russ-Hall, Kenneth A. Myers, Matthew L. Tedder, Bekim Sadikovic, Jessica A. Cooley Coleman
Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL), also known as MEF2C-related disorder or MEF2C haploinsufficiency syndrome (MCHS), is a condition caused by pathogenic variants in the Myocyte Enhancer Factor-2C (MEF2C) gene. This study aimed to identify a DNA methylation episignature specific to NEDHSIL and explore its similarities with other known episignatures. Genome-wide DNA levels were assessed in a cohort of patients with MEF2C mutations and controls, and differentially methylated CpG sites were identified. A bioinformatic analysis yielded a classifier that was trained against controls and other known episignature disorders within the EpiSign Knowledge Database. The classifier demonstrated high accuracy, sensitivity, and specificity in classifying NEDHSIL samples. Furthermore, functional annotation and comparative analysis revealed similarities between the NEDHSIL episignature and other genetic neurodevelopmental disorders. This study provides evidence for a DNA methylation episignature specific to NEDHSIL and highlights the potential utility of this epigenetic biomarker for diagnosing and understanding molecular pathophysiology of neurodevelopmental disorders associated with MEF2C mutations.
{"title":"Identification of an episignature for the MEF2C-associated syndrome","authors":"Ananília Silva, Sadegheh Haghshenas, Liselot van der Laan, Michael A. Levy, Raissa Relator, Haley McConkey, Jennifer Kerkhof, Steve A. Skinner, Laurence Faivre, James Lespinasse, Antonio Vitobello, Irene Valenzuela, Ingrid E. Scheffer, Sophie J. Russ-Hall, Kenneth A. Myers, Matthew L. Tedder, Bekim Sadikovic, Jessica A. Cooley Coleman","doi":"10.1038/s41431-025-01983-x","DOIUrl":"10.1038/s41431-025-01983-x","url":null,"abstract":"Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL), also known as MEF2C-related disorder or MEF2C haploinsufficiency syndrome (MCHS), is a condition caused by pathogenic variants in the Myocyte Enhancer Factor-2C (MEF2C) gene. This study aimed to identify a DNA methylation episignature specific to NEDHSIL and explore its similarities with other known episignatures. Genome-wide DNA levels were assessed in a cohort of patients with MEF2C mutations and controls, and differentially methylated CpG sites were identified. A bioinformatic analysis yielded a classifier that was trained against controls and other known episignature disorders within the EpiSign Knowledge Database. The classifier demonstrated high accuracy, sensitivity, and specificity in classifying NEDHSIL samples. Furthermore, functional annotation and comparative analysis revealed similarities between the NEDHSIL episignature and other genetic neurodevelopmental disorders. This study provides evidence for a DNA methylation episignature specific to NEDHSIL and highlights the potential utility of this epigenetic biomarker for diagnosing and understanding molecular pathophysiology of neurodevelopmental disorders associated with MEF2C mutations.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"53-60"},"PeriodicalIF":4.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145603309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1038/s41431-025-01984-w
Rowan Forbes Shepherd, Camella J Rising, Richard P Moser, Chloe O Huelsnitz, Patrick Boyd, Catherine Wilsnack, Alix G Sleight, William M P Klein, Allison Werner-Lin, Sadie P Hutson, Paul K J Han, Payal P Khincha
Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; Mage = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental (M = 65.8), physical (M = 67.5), and general (M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores (M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = -0.491, 95% CI -0.76, -0.22, p < 0.001) and general HRQOL (β = -0.466, 95% CI -0.77, -0.16, p = 0.004), but not mental HRQOL (p = 0.102). CC-LFS accounted for significant proportions of unique variance in general (R2adj = 17.7%, p = 0.004) and physical HRQOL (R2adj = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs' psychosocial health.
Li-Fraumeni综合征（LFS）是一种遗传性疾病，从出生起就与高多器官癌症风险相关。患有LFS的年轻人（18-39岁）经历可能对健康相关生活质量（HRQOL）产生负面影响的社会心理挑战。本研究旨在描述一种特定的社会心理挑战，关注LFS的后果（CC-LFS），并探讨CC-LFS与青少年HRQOL之间的关系。一项在线调查评估了参加国家癌症研究所研究的患有LFS的青少年的CC-LFS和HRQOL。回归分析检验了CC-LFS和HRQOL评分之间的关系，调整了年龄、癌症和精神健康挑战史。在37名受访者中（78%为女性，年龄31岁），51%有癌症病史。许多人报告了过去的精神健康挑战，包括情绪问题（70%）、抑郁/焦虑障碍（68%）和自杀意念（43%）。精神（M = 65.8）、身体（M = 67.5）和一般（M = 63.9） HRQOL的平均得分低于一般人群。CC-LFS评分越高（M = 31/50, SD = 7.2），各HRQOL域评分越低。调整协变量后，较高的CC-LFS评分与较低的身体HRQOL （β = -0.491, 95% CI -0.76, -0.22, p = 17.7%, p = 0.004）和身体HRQOL （p = 20.4%, p = 0.004）相关
{"title":"Concerns about the consequences of cancer predisposition and relationships with quality of life in young adults with Li-Fraumeni syndrome.","authors":"Rowan Forbes Shepherd, Camella J Rising, Richard P Moser, Chloe O Huelsnitz, Patrick Boyd, Catherine Wilsnack, Alix G Sleight, William M P Klein, Allison Werner-Lin, Sadie P Hutson, Paul K J Han, Payal P Khincha","doi":"10.1038/s41431-025-01984-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01984-w","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; M<sub>age</sub> = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental (M = 65.8), physical (M = 67.5), and general (M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores (M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = -0.491, 95% CI -0.76, -0.22, p < 0.001) and general HRQOL (β = -0.466, 95% CI -0.77, -0.16, p = 0.004), but not mental HRQOL (p = 0.102). CC-LFS accounted for significant proportions of unique variance in general (R<sup>2</sup><sub>adj</sub> = 17.7%, p = 0.004) and physical HRQOL (R<sup>2</sup><sub>adj</sub> = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs' psychosocial health.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1038/s41431-025-01982-y
Jana M. de Vries, Arda Arduç, Quinten Waisfisz, Maria B. Tan – Sindhunata, Brigitte HW Faas, Elisabeth van Leeuwen, Ingeborg H. Linskens, Eva Pajkrt
This study evaluates the diagnostic genetic yield in fetuses sonographically suspect of having isolated clubfoot. We conducted a retrospective study on all fetuses with apparently isolated clubfoot on initial ultrasound, examined between January 2021 and December 2024. Clubfoot was classified as isolated when no additional structural anomalies were observed on initial imaging. Among 218 cases, 140 (64%) were classified as isolated. Prenatal genetic testing was performed in 64 of these cases (46%), of which 61 (95%) underwent both copy number variant (CNV) and single nucleotide variant (SNV) analysis. In 38 of the 61 (62%) cases targeted investigation of the DMPK gene was carried out too. Pathogenic or likely pathogenic causative variants were identified in six of the 61 (9.8%) pregnancies: two of the 26 tested (7.7%) with unilateral clubfoot and four of the 35 tested (11.4%) with bilateral clubfoot. These include SNVs in TRPV4, PTPN11, BBS2, and MED13L (4/61 = 6.6%) and two CNVs, a de novo 22q11.23 deletion, and a de novo 5q21.1q31.1 deletion (2/61 = 3.3%). One case remained unsolved due to the identification of a variant of uncertain significance (VUS) in PIEZO2. Three cases revealed unsolicited findings unrelated to the indication for testing. Our findings highlight the diagnostic yield of prenatal CNV- and SNV-testing in cases of suspected isolated clubfoot, but does not support systemic testing for DMPK. Although broad genetic testing can support diagnosis and counseling, challenges remain in interpreting results and managing unsolicited findings.
{"title":"Genetic analysis in fetuses with isolated clubfoot: diagnostic insights and added value","authors":"Jana M. de Vries, Arda Arduç, Quinten Waisfisz, Maria B. Tan – Sindhunata, Brigitte HW Faas, Elisabeth van Leeuwen, Ingeborg H. Linskens, Eva Pajkrt","doi":"10.1038/s41431-025-01982-y","DOIUrl":"10.1038/s41431-025-01982-y","url":null,"abstract":"This study evaluates the diagnostic genetic yield in fetuses sonographically suspect of having isolated clubfoot. We conducted a retrospective study on all fetuses with apparently isolated clubfoot on initial ultrasound, examined between January 2021 and December 2024. Clubfoot was classified as isolated when no additional structural anomalies were observed on initial imaging. Among 218 cases, 140 (64%) were classified as isolated. Prenatal genetic testing was performed in 64 of these cases (46%), of which 61 (95%) underwent both copy number variant (CNV) and single nucleotide variant (SNV) analysis. In 38 of the 61 (62%) cases targeted investigation of the DMPK gene was carried out too. Pathogenic or likely pathogenic causative variants were identified in six of the 61 (9.8%) pregnancies: two of the 26 tested (7.7%) with unilateral clubfoot and four of the 35 tested (11.4%) with bilateral clubfoot. These include SNVs in TRPV4, PTPN11, BBS2, and MED13L (4/61 = 6.6%) and two CNVs, a de novo 22q11.23 deletion, and a de novo 5q21.1q31.1 deletion (2/61 = 3.3%). One case remained unsolved due to the identification of a variant of uncertain significance (VUS) in PIEZO2. Three cases revealed unsolicited findings unrelated to the indication for testing. Our findings highlight the diagnostic yield of prenatal CNV- and SNV-testing in cases of suspected isolated clubfoot, but does not support systemic testing for DMPK. Although broad genetic testing can support diagnosis and counseling, challenges remain in interpreting results and managing unsolicited findings.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"193-200"},"PeriodicalIF":4.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01982-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s41431-025-01968-w
Daniel Sheen, Amanda Willis, Zoe Fehlberg, Melissa Southey, Ilias Goranitis, Mary-Anne Young
The increasing use of genomic testing in clinical and research contexts raises how best to manage additional findings (AFs). This systematic review of the preferences of clinical patients and research participants for what and how AFs should be returned, aims to inform development of guidelines and policies that are inclusive of test recipients. Framework analysis was used to systematically review qualitative and quantitative studies exploring preferences for AFs in clinical and research contexts and identify key themes. Eighty-seven studies were included involving a total of 71,486 study participants. The right to choose whether and what AFs to receive was highly supported. Actionable findings and findings with familial implications were highly desired across studies. Additionally, a substantial number of studies identified mixed interest in findings currently not returned, including non-actionable findings and variants of unknown significance (VUS). Penetrance and certainty influenced perceived relevance and decisions regarding what to receive, with varying thresholds identified within studies. This review identified a consistent desire for systematic support for test recipient decision-making and managing AFs. The findings of this review support existing emphasis on recipient choice. However, recipient strength of preference for a broad variety of findings indicates that a minimum acceptable return of actionable findings should be established in national guidelines and the feasibility of offering other types of findings should be explored.
{"title":"Systematic review of preferences for additional findings from genomic testing","authors":"Daniel Sheen, Amanda Willis, Zoe Fehlberg, Melissa Southey, Ilias Goranitis, Mary-Anne Young","doi":"10.1038/s41431-025-01968-w","DOIUrl":"10.1038/s41431-025-01968-w","url":null,"abstract":"The increasing use of genomic testing in clinical and research contexts raises how best to manage additional findings (AFs). This systematic review of the preferences of clinical patients and research participants for what and how AFs should be returned, aims to inform development of guidelines and policies that are inclusive of test recipients. Framework analysis was used to systematically review qualitative and quantitative studies exploring preferences for AFs in clinical and research contexts and identify key themes. Eighty-seven studies were included involving a total of 71,486 study participants. The right to choose whether and what AFs to receive was highly supported. Actionable findings and findings with familial implications were highly desired across studies. Additionally, a substantial number of studies identified mixed interest in findings currently not returned, including non-actionable findings and variants of unknown significance (VUS). Penetrance and certainty influenced perceived relevance and decisions regarding what to receive, with varying thresholds identified within studies. This review identified a consistent desire for systematic support for test recipient decision-making and managing AFs. The findings of this review support existing emphasis on recipient choice. However, recipient strength of preference for a broad variety of findings indicates that a minimum acceptable return of actionable findings should be established in national guidelines and the feasibility of offering other types of findings should be explored.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 1","pages":"10-26"},"PeriodicalIF":4.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01968-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s41431-025-01977-9
Amelia Warren, Demetra Andreou, Dean Warren, Jack Wieland, Anna Mantzouratou
Endometriosis is a chronic, estrogen-driven inflammatory disorder affecting approximately 10% of reproductive-aged women globally. Despite increasing genomic insights into advanced-stage disease, the genetic underpinnings of early-stage endometriosis remain poorly understood, limiting opportunities for timely diagnosis and intervention. This study explores the contribution of regulatory variants, including those derived from ancient hominin introgression, and their interaction with modern environmental exposures in shaping endometriosis susceptibility. We conducted a dual-phase literature review to identify genes implicated in endometriosis pathophysiology and endocrine-disrupting chemical (EDC) sensitivity. Five genes (IL-6, CNR1, IDO1, TACR3, and KISS1R) were selected based on tissue expression, pathway involvement, and EDC reactivity. Whole-genome sequencing (WGS) data from the Genomics England 100,000 Genomes Project were analysed in nineteen females with clinically confirmed endometriosis. Variant enrichment, co-localisation, and linkage disequilibrium analyses were conducted, and functional impact was evaluated using public regulatory databases. Six regulatory variants were significantly enriched in the endometriosis cohort compared to matched controls and the general Genomics England population. Notably, co-localised IL-6 variants rs2069840 and rs34880821—located at a Neandertal-derived methylation site—demonstrated strong linkage disequilibrium and potential immune dysregulation. Variants in CNR1 and IDO1, some of Denisovan origin, also showed significant associations. Several of these variants overlapped EDC-responsive regulatory regions, suggesting gene-environment interactions may exacerbate risk. These findings propose a novel perspective of endometriosis susceptibility, in which ancient regulatory variants and contemporary environmental exposures converge to modulate immune and inflammatory responses. This integrative approach identified new potential biomarkers for early-stage detection of endometriosis.
{"title":"Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants","authors":"Amelia Warren, Demetra Andreou, Dean Warren, Jack Wieland, Anna Mantzouratou","doi":"10.1038/s41431-025-01977-9","DOIUrl":"10.1038/s41431-025-01977-9","url":null,"abstract":"Endometriosis is a chronic, estrogen-driven inflammatory disorder affecting approximately 10% of reproductive-aged women globally. Despite increasing genomic insights into advanced-stage disease, the genetic underpinnings of early-stage endometriosis remain poorly understood, limiting opportunities for timely diagnosis and intervention. This study explores the contribution of regulatory variants, including those derived from ancient hominin introgression, and their interaction with modern environmental exposures in shaping endometriosis susceptibility. We conducted a dual-phase literature review to identify genes implicated in endometriosis pathophysiology and endocrine-disrupting chemical (EDC) sensitivity. Five genes (IL-6, CNR1, IDO1, TACR3, and KISS1R) were selected based on tissue expression, pathway involvement, and EDC reactivity. Whole-genome sequencing (WGS) data from the Genomics England 100,000 Genomes Project were analysed in nineteen females with clinically confirmed endometriosis. Variant enrichment, co-localisation, and linkage disequilibrium analyses were conducted, and functional impact was evaluated using public regulatory databases. Six regulatory variants were significantly enriched in the endometriosis cohort compared to matched controls and the general Genomics England population. Notably, co-localised IL-6 variants rs2069840 and rs34880821—located at a Neandertal-derived methylation site—demonstrated strong linkage disequilibrium and potential immune dysregulation. Variants in CNR1 and IDO1, some of Denisovan origin, also showed significant associations. Several of these variants overlapped EDC-responsive regulatory regions, suggesting gene-environment interactions may exacerbate risk. These findings propose a novel perspective of endometriosis susceptibility, in which ancient regulatory variants and contemporary environmental exposures converge to modulate immune and inflammatory responses. This integrative approach identified new potential biomarkers for early-stage detection of endometriosis.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"34 2","pages":"243-251"},"PeriodicalIF":4.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01977-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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